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Research Themes Infectious diseases

Microbial Pathogenesis: Measles Virus Attachment

SBKB [doi:10.1038/sbkb.2012.118]
Featured Article - January 2013
Short description: The third structure of a host receptor bound to measles virus hemagglutinin pinpoints a hydrophobic lock hole.

Footprints of nectin-4v, SLAM and CD46 binding on the surface of a MV-H protein, with the β4-β5 groove facing from the page (β4 blade to the left, β5 to the right). Shared residues and the hydrophobic pocket are labeled.

Measles outbreaks have become quite rare in developed countries, but the disease still has a high mortality rate among children worldwide. There is no treatment for this highly contagious disease. Measles-derived viral vectors have emerged as top candidates for oncolytic gene therapy. It is thus critical to understand how precisely measles virus binds to host cells, at molecular and atomic levels.

To date, three receptors have been identified for the glycoprotein responsible for measles attachment to host cells, the measles virus hemagglutinin (MV-H). On immune cells such as macrophages and dendritic cells, wild-type MV-H binds to the signaling lymphocytic activation molecule (SLAM), whereas vaccine strains predominantly use CD46 as an alternative receptor. Most recently, nectin-4, expressed on the basal side of polarized epithelial cells, was found to be the third MV-H receptor required for aerosol transmission of the virus.

Previous crystal structures of MV-H in complex with SLAM (PDB 3ALW) or CD46 (PDB 3INB) revealed that these receptors bind to a side groove in the six-bladed β-propeller fold of the MV-H head domain. However, it remained unclear whether nectin-4 also binds to the same groove or elsewhere in the β-propeller.

Gao and colleagues have now solved the structure of MV-H bound to the membrane-distal V-set immunoglobulin domain of nectin-4 (nectin-4v) at 3.1 Å resolution (PDB 4GJT). Each asymmetric unit consists of two nectin-4v molecules located on opposite sides of the MV-H β-propeller, but only the binding on the concave side groove—composed of β4-β5 blades—is functionally relevant, as supported by mutagenesis evidence. This interface is dominated by hydrophobic interactions.

The binding site of nectin-4 on MV-H is situated between those for SLAM and CD46. Superimposing the footprints of all three receptors on MV-H unveils an overlap around a small hydrophobic pocket at the center of the β4-β5 groove. Nectin-4v and CD46 both insert a loop deeply into that pocket, whereas SLAM only lays over it, explaining the highest affinity of MV-H for nectin-4, despite the smallest binding surface among the receptors.

The structural knowledge of this crucial measles virus-host interaction and the identification of the conserved hydrophobic pocket in MV-H can be harnessed for therapeutic goals, as it will facilitate molecular design of anti-measles therapy.

Wayne Peng


  1. X. Zhang et al. Structure of measles virus hemagglutinin bound to its epithelial receptor nectin-4.
    Nat. Struct. Mol. Biol. (2 December 2012). doi:10.1038/nsmb.2432

  2. M.D. Mülebach et al. Adherens junction protein nectin-4 is the epithelial receptor for measles virus.
    Nature. 480, 530-533 (2011). doi:10.1038/nature10639

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